This patent relates to the general field of therapeutic products and methods to inhibit certain disease states related to the general medical field of human and veterinary pharmacology wherein the activation of the lipoxygenase pathways contribute to the pathological condition. Agents which inhibit or modulate the 5-lipoxygenase or 12-lipoxygenase pathways are known to be useful in the medical arts. Agents with little or no toxicity that inhibit systemic or dermatological inflammations are useful in the healing arts. This patent also relates to the field of pigmented agents useful in the aquaculture industry, wherein pigmented ingredients must be incorporated into aquatic feeds in order to bring about a deposition of color either in the flesh of the animal, or on the skin or shell thereof.
More particularly, the present invention concerns certain novel lipids derived from the class Holothuridea, or sea cucumber, and especially, the Cucumaria frondosa variety found in Maine and the North Atlantic. Any species of sea cucumber parts will suffice for raw material from which to extract the compounds of the present invention. The oils of such sea cucumbers from any species can be used for pigmentation of aquatic species by incorporation into feeds, as well as for the treatment or amelioration of diseases in which products of lipoxygenase enzyme activity or the reaction of leukotrienes contribute to the pathological condition. That is, the novel lipids derived from any class or species of sea cucumber inhibit lipoxygenase enzymes and/or bind leukotriene receptors. Lipoxygenase enzymes are well known in the arachidonic acid cascade. These oils, designated RED OIL and GOLD OIL, can be used as-is for immunosuppressive purposes and also provide raw materials from which to derive ingredients of immunosuppressive drugs suitable to ameliorate immune responses due to organ transplant or autoimmune response in diseases such as lupus or rheumatoid arthritis. These oils or derivatives thereof from molecular distillation are suitable xe2x80x98as-isxe2x80x99 or may be further fractionated by means known to the arts and can be used to reduce, suppress, inhibit, or prevent unwanted immune responses, e.g., in humans or animals requiring immunosuppression. Examples of such situations include. but are not limited to, treatment or prevention of autoimmune diseases such as diabetes, lupus, and rheumatoid arthritis. Immunosuppression is also frequently needed in conjunction with organ transplants. Immunosuppressive agents can also be utilized when a human or animal has been, or may be, exposed to superantigens or other factors known to cause overstimulation of the immune system. The compounds of the subject invention are also useful as standards to assess the activity of other putative immunosuppressive agents. The subject invention further pertains to pharmaceutical compositions containing these compounds. These oils are also shown by the present invention to inhibit angiogenesis, as shown in the chick chorioallantoic membrane assay (Knighton et al., 1977). The pigmented oil, designated for purposes of this patent as RED OIL. has been shown to contain surprising amounts of the carotenoids, canthaxanthin and astaxanthin, and is suitable for adding to commercial fish feeds in order to bring color deposition to the flesh or skin of particular species in need of same.
The present invention relates to novel compounds, pharmaceutical compositions and methods of use for the treatment of diseases in which the 5- and 12-lipoxygenase activity contributes to the pathological condition. The present invention also relates to products derived from the lipid fractions of sea cucumber tissue which ameliorate immune responses and which can also be incorporated into aquatic diets for the purpose of imparting color to the flesh or skin of such fish or shrimp. Although there have been reports in the literature concerning marine lipids from certain fish in the treatment of various arthritis related diseases, sea cucumber lipids have never been included in any studies, nor is there any evidence that the inflammation inhibitory mechanisms known of vertebrate fishes in mammalian systems is relevant to this invention (DeLuca et al., 1995). It is also known that certain marine sponges and ascidians possess immunomodulatory or immunosuppressive activities, but there are no reports in the field of marine pharmacology that sea cucumber lipids have been discovered to possess any such inhibitory activities useful in the medical arts (Konig and Wright, 1995).
More particularly, the compounds defined below inhibit the 5-lipoxygenase pathway and the 12-lipoxygenase pathway in mammals. Lipoxygenase pathway products such as the leukotrienes B4, C4, D4 and E4, 5-hydroxyeicosatetraenoic acid, 5-hydroperoxyeicosatetraenoic acid and 12-hydroxyeicosatetracnoic acid are related to the above described conditions. Specific conditions for use of the present novel lipoxygenase-inhibiting compounds, pharmaceutical compositions thereof and the novel method of use in accordance with the present invention include allergy; asthma; arthritis; skin disorders including psoriasis, a topic dermatitis and acne; inflammation-including inflammatory bowel diseases or pain; various cancers including prostate, lung, colorectal, and skin; and cardiovascular disorders including myocardial ischemia and infarction, angina, arrhythmias, stroke, migraine and atherosclerosis.
The compounds of the present invention are derived from the lipid fractions of sea cucumber of any species or sub-phyla; from the de-pigmented fraction of such lipid fraction; from the molecular distillation phases as are known to those skilled in the arts; or from the chromatographic column separations of same; from the epidermal. dermal, anterior, posterior, or intestinal mass including respiratory trees, gonads, cuverian tubules or polian vesicles of any sea cucumber.
Sea cucumbers of various species provide medically active fractions useful to die healing arts. U.S. Pat. No. 5.519,010 teaches that a de-polymerized polysaccharide is useful as an anti-coagulant. U.S. Pat. No. 5,770,205 by Collin teaches that sea cucumber tissues extracted by various methods possess anti-inflammatory activity useful in the human and veterinary medical arts. Glycosides from sea cucumber organs have been shown to contain anti-cancer agents (Miyamoto et al., 1990). None of the above describe a lipid from sea cucumber which inhibits any lipoxygenase pathway, nor inflammation, nor describes any utility of such sea cucumber-derived agents to inhibit pathological disease conditions in which lipoxygenase products, isomers, or metabolites contribute to such condition. Nor do any of the above patents present any art wherein such lipids provide an immunomodulatory activity in a mammal.
The present invention teaches that both the pigment-rich lipid materials and the de-pigmented lipid materials and the Light Phases recovered from molecular distillation of any of the pigmented or de-pigmented sea cucumber lipid materials are able to inhibit the 5-lipoxygenase enzyme activity in human neutrophils and the 12-lipoxygenase enzyme in human platelets.
There are currently many patents describing agents which purport to inhibit the leukotriene and 5-lipoxygenase and 12-lipoxygenase pathways in mammals. Some of these compounds are effective, and some have toxic side-effects or cannot be cost-effectively produced. It is an object of the present invention that the production of sea cucumber oils and their derivatives which can be incorporated into ointments, suppositories, and embodied into orally administered or injected medicines or into medicine administered by other means, provides a cost effective and readily available means to modulate the leukotriene pathway in mammals and thus will contribute to the therapeutic treatment of such diseases as cancer, psoriasis, atopic dermatitis, etc. in which leukotrienes, LTB4, 5-HETE and 12-HETE contribute to the pathological condition.
Therapeutic application of the new compounds and compositions containing them can be contemplated to be accomplished by any suitable therapeutic method and technique presently or prospectively known to those skilled in the art. Further, the compounds of the present invention have use as starting materials or intermediates for the preparation of other useful compounds and compositions exhibiting more potent activity.
It is an object of the present invention to provide to the arts pharmaceutical compositions comprising, as active ingredients, an effective amount of one or more of the novel compounds herein described. An object of the present invention is to provide to the art new compounds which are useful as immunomodulatory agents through their inhibitory activities of the lipoxygenase pathways in mammals and through their inhibitory activities of the lymphocyte proliferation pathways of the mammalian immune system, as well as ingredients which are useful in aquatic diets for the pigmentation of marine life. Molecular distillation or other separatory technique fractions comprising the LIGHT PHASES so called of the extracted sea cucumber oils native to sea cucumber tissues have been shown to be inhibitory of the lipoxygenase pathways. Also, the HEAVY PHASES from molecular distillation of these same oils show similar activities. Isolations of more active moieties of these pathways can be produced through column chromatography, for example, or other methods known to those skilled in the lipid biochemistry arts. Therefore it is an object of the present invention to provide a raw material and active intermediates for such isolations if more potent or specific fractions are desired.
The compounds of this invention inhibit 5-lipoxygenase and 12-lipoxygenase activity in mammals, which inhibitory activity has been associated with antiallergic, anti-inflammatory and antihyperproliferative activity. The compounds of the invention are thus useful for the treatment of allergic diseases as discussed above, inflammatory diseases of the epithelium, heart-bum, cancer and hyperproliferative skin diseases. They have also been shown to inhibit lymphocyte proliferation in human blood.
The inflammatory diseases which may be treated include arthritis, bursitis, tendinitis, gout and inflammatory bowel disease.
xe2x80x9cHyperproliferative skin diseasexe2x80x9d means any condition, a symptom of which is accelerated skin cell production, flaking, scales or papular lesions. Examples of hyperproliferative skin diseases include, for example, psoriasis, lichenified eczema, dandruff and the like.
The compounds of this invention can be administered in any number of conventional dosage forms, e.g. topical, oral, parenteral, rectal, transdermal, inhalation and the like. Oral or rectal dosage forms include capsules, tablets, pills, powders, cachets and suppositories. Liquid oral dosage forms include solutions and suspensions. Parenteral preparations include sterile solutions and suspensions. Inhalation administration can be in the form of a nasal or oral spray, or by insufflation. Topical dosage forms can be creams, ointments, lotions, transdermal devices (e.g. of the conventional patch or matrix type) and the like and are preferred for treating hyperproliferative skin diseases.
The formulations and pharmaceutical compositions contemplated by the above dosage forms can be prepared with conventional pharmaceutically acceptable excipients and additives using conventional techniques. Such pharmaceutically acceptable excipients and additives are intended to include carriers, binders, flavorings, buffers, thickeners, color agents, stabilizing agents, emulsifying agents, dispersing agents, suspending agents, perfumes, preservatives, lubricants, etc.
Suitable pharmaceutical acceptable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting waxes, cocoa butter and the like. Capsules can be made wherein the active compound is inserted into pharmaceutically acceptable capsules as a carrier. The active compounds of this invention can be mixed with pharmaceutically acceptable excipients or can be used in finely divided powder form without excipients for inclusion into capsules. Similarly, cachets are included as are liposomes as are known to those skilled in the arts.
Liquid form preparations include solutions, suspensions and emulsions. As an example, it may be mentioned of water or water-propylene glycol solutions for parenteral injection. Liquid preparations can also be formulated in solution in polyethylene glycol and/or propylene glycol, which may contain water. Aqueous solutions suitable for oral use can be prepared by adding the active component in water and adding suitable colorants, flavors, stabilizing, sweetening, solubilizing and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the active component in the oil form within an emulsifier such as TWEEN-80 as is known in the industry familiar with oil/water emulsions.
Formulations for topical application, e.g., for use in treating hyperproliferative skin diseases, may include the above liquid forms, as well as creams, aerosols, sprays, dusts wherein the oil is admixed with a suitable carrier, lotions and ointments which are prepared by combining the active ingredient according to this invention with conventional pharmaceutical acceptable diluents and carriers commonly used in topical formulations. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Such bases may, for example, include water and/or an oil such as liquid paraffin or beeswax or a vegetable oil such as peanut oil or castor oil. Thickening agents which may be used according to the nature of the base include soft waxes, aluminum stearate, cetostearyl alcohol, propylene glycol, polyethylene glycol, woolfat, hydrogenated lanolin, etc.
Lotions may be formulations with an aqueous or oil base and will, in general, also include one or more pharmaceutically acceptable stabilizing agents, emulsifying agents, dispersing agents, suspending agents, thickening agents, coloring agents, perfumes and the like.
The topical pharmaceutical compositions may also include one or more preservatives or bacteriostatic agents, e.g., methyl hydroxybenzoate, propyl hydroxybenzoate, chlorocresol, benzalkonium chlorides, etc.
The topical pharmaceutical compositions may also contain an active compound of this invention in combination with other active ingredients such as antimicrobials, particularly antibiotics, anesthetics, analgesics and antipruritic agents such as zinc pyrithione.
The compounds of this invention may also be deliverable transdermally for systemic distribution. The transdermal compositions can take the form of creams, lotions and/or emulsions and be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
The compounds of this invention may be administered by any conventional mode of administration by employing an anti-allergic, anti-inflammatory or antihyperproliferative effective amount of a compound of this invention for such mode. The dosages may be varied depending upon the requirements of the patient in the judgment of the attending clinician, the severity of the condition being treated and the particular compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art. Treatment can be initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage should be increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.
Thus, depending on the mode, dosages of from about 0.1 to about 500 mg/kg of body weight per day may be administered. For example, when administered orally they exhibit antiallergy activity at dosages of from about 0.5 to about 200 mg/kg of body weight and preferably about 50 to about 100 mg/kg of body weight; when administered by inhalation, the compounds exhibit antiallergy activity at dosages of 0.1 to 5 mgs per puff, and one to four puffs may be taken every 4 hours.
The compounds of this invention can be administered by any conventional mode of administration, to obtain the anti-inflammatory activity by employing an anti-inflammatory effective amount of a compound of this invention. The compounds of this invention, as an anti-inflammatory agent, may be administered at doses of about 0.1 to about 500 mg/kg of body weight per day, and preferably about 5 to about 200 mg/kg per day. Preferably the total dosages are administered in 2 to 4 divided doses per day. For example, an oral dosage range of from about 5 mg/kg of body weight per day to about 50 mg/kg of body weight per day in divided doses taken at about 4 hour intervals may be used.
When administered for the treatment of hyperproliferative skin disease, the compounds of this invention may be administered topically, orally, rectally or parenterally, preferably topically. When administered topically, the amount of compound administered varies widely with the amount of skin being treated, as well as with the concentration of active ingredient applied to the affected area. Preferably, topical compositions contain from about 0.10 to about 10 percent by weight of the active ingredient and are applied as needed according to the judgment of the attending clinician. When administered orally, the compounds of RED OIL and GOLD OIL are effective for the treatment of hyperproliferative skin disease at daily doses ranging from about 0.1 mg/kg to about 500 mg/kg of body weight, preferably from about 5 mg/kg to about 100 mg/kg, which may be administered in divided doses. When administered rectally, the compounds of this invention may be administered in daily doses ranging from about 0.1 mg/kg to about 100 mg/kg.
As a result of the administration of a compound of this invention, a remission of the symptoms of the psoriatic patient, in most cases, can be expected. Thus, one affected by psoriasis can expect a decrease in scaling, erythema, size of the plaques, pruritus, and other symptoms associated with psoriasis. The dosage of medicament and the length of time required for successfully treating each individual psoriatic patient may vary, but those skilled in the art of medicine will be able to recognize these variations and adjust the course of therapy accordingly.
Lipoxygenase Systems
Arachidonic acid serves as the biological precursor for a family of physiologically active eicosanoids. These include products derived from the action of cyclooxygenase such as the class of prostaglandin-E and -F compounds, thromboxanes, and prostacyclin, and products derived from the action of lipoxygenase enzymes such as hydroxy- and hydroperoxyeicosatetraenoic acids and the leukotrienes.
These lipoxygenase products have been shown to be highly potent stercospecific inducers of polymorphonuclear leukocyte migration or chemotaxis, lysosomal enzyme release, and degranulation. Additionally, these products induce the contraction of smooth muscle such as vascular and pulmonary tissue, and induce the generation of additional inflammogens such as thromboxanes A2 and prostacyclin. Lipoxygenase products also interact with vasodilator prostanoids and other mediators, leading to the enhancement or amplification of the inflammatory response.
Leukotrienes and the hydroxy and hydroperoxyeicosatetraenoic acids play a major role in the pathogenesis of many disease conditions. These compounds have been found in synovial fluid of rheumatoid joints, in involved skin of psoriatic patients, in inflamed colonic tissue, and at elevated levels in ischemic myocardial tissue. They are also mediators of allergic and asthmatic conditions.
A role for 5-HETE in stimulating growth of a number of different types of tumors has recently been demonstrated in a number of publications. For example, the addition of arachidonic acid to cultured human prostate cancer cells resulted in a significant increase in cell growth and an increased biosynthesis of 5-hydroxycicosatetraenoic acid (5-HETE) (Ohosh and Myers, 1997). This increased growth was blocked by the 5-lipoxygenase (5-LO) inhibitors AA681 and MK886, but not by the 12-LO inhibitors, baicalein and N-benzyl-N-hydroxy-5-phenylpentanamide (BHPP) nor by cyclooxygenase (COX) inhibitors. Furthermore, the addition of 5-HETE, but not other products of the 5-LO pathway such as leukotriene B4, to cells not only stimulated cell growth but also reversed the effect of MK886. Similar findings have also been observed in other types of cancer cells both in vitro and in vivo. For example, in human breast cancer (HS578T) cell line, the LO inhibitors nordihydroguaiarctic acid (NDGA) and esculetin inhibited cell growth, but the COX inhibitor piroxicam had no effect (Hofmanova et al., 1996). In the murine adenocarcinoma cell line (MAX) and mice transplanted with MAC cells, 5-LO inhibitors BWA4C (an acetohydroxamicacid with die general formula R-CONHOH) and BWB70C (an acetohydroxamic acid derivative) inhibited tumor cell growth and 5-HETE production (Hussey and Tisdale, 1996). Furthermore, in in vivo studies in A/J mice with adenoma induced by urethane, administration of NDGA significantly decreased lung adenoma cell number (Moody et al., 1998) and in murine adenocarcinoma, BWA4C and BWB70C were also shown to decrease MAC26 and MAC 16 cell growth by effects on both 5- and 12-HETE production (Hussey and Tisdale. 1996).
12-HETE
Increasing evidence suggests that 12-HETE, generated by platelets and tumor cells is a crucial molecule in promoting tumor metastasis. It enhances tumor cell induced platelet aggregation and tumor cell adhesion to subendothelial matrix by increasing expression of surface integrins, induces endothelial cell retraction, and increases tumor cell motility, all of which are important steps in tumor cell metastasis (Honn et al., 1994). In vitro studies have shown that the 12-LO inhibitor BHPP abolishes the above effects of both endogenously and exogenously added 12-HETE (Honn et al., 1992; Chen at al., 1994). It has also been demonstrated that 12-HETE production is a good indicator of tumor cell metastatic potential. For example, 12-HETE mRNA levels are elevated in prostate cancer cells compared with normal cells, and this increase in mRNA level correlates with advanced stages and poor differentiation of cancer cells (Gao et al., 1995). In further studies, it has been shown that rat Walker carcinoma (W256) and mouse melanoma (B16a) cells metabolize arachidonic acid (AA) to 12-HETE and 5-HETE and, that in experimental metastasis, utilization of BHPP decreases colony formation in the lung (Chen et al., 1994; Liu et al., 1994).
Compounds, pharmaceutical and nutraceutical compositions in accordance with the present invention inhibit lipoxygenase or the biosynthesis or biochemical action of leukotrienes and, therefore, are useful in the treatment or amelioration of a number of diseases whose pathogenesis involves the production of the leukotrienes and other lipoxygenase-derived products such as 5-HETE and 12-HETE, and leukotriene B4 (LTB4). These lipoxygenase inhibitors aid in the prevention of tissue damage and inflammation which result from infiltration of leukocytes, release of tissue-digesting lysosomal enzymes, and changes in the permeability and contractile state of smooth muscle tissue.
Specific conditions in which such lipoxygenase-inhibiting or leukotriene-antagonizing compounds and pharmaceutical compositions in accordance with the present invention are useful include allergy: asthma; arthritis; skin disorders including psoriasis and acne; inflammation; inflammatory bowel diseases, pain, and cardiovascular disorders including myocardial ischemia and infarction, angina, arrhythmias, stroke, atopic dermatitis, atherosclerosis and cancers of various etiologies including cancers of the prostate, lung, skin and digestive tract.
Angiogenesis Inhibition by RED OTT, and GOLD OIL of the Present Invention
There has been much scientific interest in the search for new inhibitors of angiogenesis with the view that this inhibition of new blood vessels will limit the growth of neoplastic tumors which depend on new vascular growth. As a normal cell develops into a solid tumor, it undergoes a series of changes. At the physiological level, growth is enhanced, immunity evaded, and neovascularization induced. Neovascularization or angiogenesis appears to be a prerequisite for tumor growth. Experimental solid tumors are unable to grow beyond a few millimeters in thickness without a blood supply. Most natural solid tumors elaborate angiogenic factors that attract the new blood vessels on which they depend. Thus, there has been a continuing research effort directed toward the questions of what it is that may prevent rampant capillary proliferation and what maintains the quiescent state of the capillary endothelial cells of normal tissues.
An additional object of the present invention is to provide a composition of matter and a method of inhibiting angiogenesis in a warm-blooded animal in need of such treatment, which comprises administering to said warm-blooded animal a therapeutically effective amount of a composition comprising the isolated RED OIL or GOLD OIL, or LIGHT or HEAVY Phases from molecular distillation processes as described in the following sections.
Carotenoids from Sea Cucumber Tissues
Carotenoids from sea cucumbers have been mentioned in various scientific journal articles, to wit: Matsuno et al . (1995) reported the occurrence of astaxanthin as the major carotenoid in the gonads of the sea cucumbers Holothuria leucospilota and Stichopus japonicus, and beta carotene, echinenone, canthaxanthin and zeaxanthin were identified from the gonad of H. leucospilota and S. japonicus. On the other hand, astaxanthin and the esters, canthaxanthin, phoenicoxanthin and echinenone, were isolated by Bullock and Dawson (1970) from the red body wall of Psolus fabrichii. Tsushima et al. (1996) reported on the novel marine di-Z carotenoids, cucumariaxanthins A, B and C from the sea cucumber Cucumaria japonica. Findlay et al. (1983a) reported on canthaxanthin from tile species, Cucumaria frondosa. None of these reports provide any means whereby to utilize such carotenoids for any aquaculture or medical or health food industry applications, and none provide methods to concentrate such pigmented lipid fractions.
U.S. Pat. No. 4,692,280 by Spinelli, Stout and Nilsson describes a method for obtaining purified fish oils (after initial extraction from fish tissues) using supercritical carbon dioxide, and is incorporated herein by reference for the purpose of describing said methods. This patent does not disclose a means of obtaining sea cucumber lipid fraction purification through the supercritical purification methodologies set forth in the patent.
Thus, there is no prior art for the efficient and large scale removal of lipid fractions, and none directed at obtaining usable carotenoid or non-carotenoid lipid fractions of sea cucumber tissue.
It is an object of the present invention to provide a means to recover usable pigmented lipid fractions and pigment-free lipid fractions from the intestinal gut material and/or body walls from sea cucumbers, especially from the species Cucumaria frondosa. It is a further object of the present invention to disclose a composition of matter which is the pigmented lipid fraction and a de-pigmented lipid fraction resulting from such means of recovery. The resultant pigmented lipid fraction, obtained by an acetone or alcohol solvent extraction with commercial extraction equipment, such as the Crown 2 Extractor (Crown Iron Works, Chicago, Ill.), as is used in the soy-bean oil extraction arts, provides a pigmented material rich in canthaxanthin and astaxanthin at approximately 4,500 parts per million, and is useful in the aquaculture industry as a feed ingredient. After lipid extraction, the dry, de-lipidized tissue can be utilized as a high-protein meal or hydrolysate with surprising levels of essential amino acids.
The present invention sets forth methods and compositions of matter for the industrial extraction of novel pigmented and non-pigmented lipid compounds obtainable from sea cucumber gut or body-wall tissue in wet or dry raw material conditions. The compounds of the present invention are able to be used as pigmenting additives in aquatic diets or as medically therapeutic agents in mammals, and are produced by molecular distillation techniques, solvent extraction techniques on industrial scales, column chromatography techniques and through preparative high pressure liquid chromatography techniques that are described herein.
The compounds of this invention demonstrate anti-inflammatory activity made apparent by the low percent increase in ear weight in murine models of inflammation and when applied topically, and by the results of inhibition of adjuvant induced inflammation in tile hind paws of rats, as well as from anecdotal reports of subjective benefit from humans.
The compounds of this invention, the RED OIL and GOLD OIL and the molecular distillation fractions thereof are used to treat allergies in mammals (e.g. humans or dogs) and a preferred use is for treating allergic chronic inflammations of the dermis of such mammals, and with appropriate transdermal carrier compounds, as inhibitors of arthritic inflammatory conditions wherein the oils of the present invention are carried transdermally to the sites of lipoxygenase all activation locally. An additional preferred use is for treating allergic chronic obstructive lung disease. Chronic obstructive lung disease as used herein means disease conditions in which the passage of air into and out of the lungs is obstructed or diminished such as is the case in asthma, allergic or seasonal rhinitis, and/or bronchitis and the like. Treatment of psoriasis, acne, arthritis, or cancer can be accomplished by use of the compounds of the present invention as topical compounds as well as by oral administration.
Therefore, an additional object of the present invention pertains to the immunosuppressive use of the RED OIL and GOLD OIL isolated from sea cucumber tissues, and various derivatives and analogs of these compounds. These compounds can be used to reduce, suppress, inhibit, or prevent unwanted immune responses. Advantageously, this immunosuppression can be achieved without cytotoxicity. Therefore, these compounds are useful for treatments of humans or animals requiring immunosuppression. Examples of such situations include, but are not limited to, treatment or prevention of autoimmune diseases such as diabetes, lupus, and rheumatoid arthritis. Immunosuppression is also frequently needed in conjunction with organ transplants. Immunosuppressive agents can also be utilized when a human or animal has been, or may be, exposed to superantigens or other factors known to cause overstimulation of the immune system. The compounds of the subject invention are also useful as standards to assess the activity of other putative immunosuppressive agents. The subject invention further pertains to pharmaceutical compositions containing these compounds.
As pigment additives, the various pigmented oils can be added to fish or shrimp feeds at various inclusion rates depending on the carotenoid content of the oil or the desire for certain intensities of color in particular aquatic species being fed the pigmented diet.